Metabolic Cost of Rapid Adaptation of Single Yeast Cells Under Unforeseen Challenge

Introductory paragraph Cells are known to be able to adapt to changing environments. In the classical neo-Darwinian picture, random genetic mutations cause phenotypic variations, enabling adaptation to the new environment. In addition, non-genetic pathways are increasingly believed to play an important role in rapid adaptation, notably in the emergence of drug resistance 1–7 . However, the coupling between metabolism and adaptation has never been addressed at the single-cell level. Here we show that following a severe, unforeseen challenge, yeast cells display a wide range of metabolic rates, and can adapt rapidly, with the rate of adaptation being controlled by the metabolic rate. We simultaneously measured metabolism and division of thousands of individual Saccharomyces cerevisiae cells, using a droplet-based microfluidic system 8 . Remarkably, the majority (~88%) of the cells, while not dividing, nevertheless displayed a metabolic response with a wider diversity of metabolic rates (CV=0.60) than unchallenged cells (CV=0.24). Over the course of the 70 h experiment, a sizeable fraction of cells (53%) switched state either by accelerating their metabolism (4%, metabolic recovery) or arresting it (49%). The time of acceleration was inversely proportional to the initial metabolic rate and a large fraction (73%) of these recovering cells resumed division, on average at the same time they accelerate their metabolism. This indicates that adaptation is an active process, requiring the consumption of a characteristic amount of energy. The adaptation rate (10 −3 cells/h) is orders of magnitude higher than expected based on known mutation rates, suggesting an epigenetic origin. The demonstration that metabolic trajectories predict a priori adaptation events offers the first evidence of the tight energetic coupling between the metabolic and regulatory processes in adaptation. This process allows S. cerevisiae to adapt on a physiological time scale, but related phenomena may also be important in other processes, such as cellular differentiation, cellular reprogramming and the emergence of drug resistance in cancer.